YOUR INTRODUCTION TO

SELECTED SAFETY INFORMATION Do not take NIVESTYMTM if you have had a serious allergic reaction to human granulocyte colony-stimulating factors (G-CSFs) such as filgrastim products or pegfilgrastim products.

Please see Important Safety Information and Indications on pages 8-11 and accompanying full Prescribing Information, including Patient Information. NIVESTYM is FDA-approved to:

WHAT IS • Help reduce the risk of infection caused by low white blood cell count (with fever) in patients with nonmyeloid cancer NIVESTYM? who are receiving chemotherapy, which can increase the risk of low white blood cell count (with fever)

• Reduce the length of time of low white blood cell count (with fever) in patients with acute myeloid leukemia NIVESTYM is an FDA-approved, man-made form of (AML), after receiving chemotherapy treatment granulocyte colony-stimulating factor (G-CSF), which is a substance produced by the body. • Reduce the length of time of low white blood cell count and its effects (such as increased risk of infection) in NIVESTYM stimulates the growth of neutrophils, patients with nonmyeloid cancer who are receiving a type of white blood cell important in the body’s chemotherapy followed by bone marrow transplantation fight against infection. • Collect immature white blood cells from patients’ own blood

• Reduce the number of times and duration of severe low white blood cell count and its effects (for example fever, infections, mouth sores) in people who are born with conditions that lead to an increased chance of experiencing symptoms from their low white blood cell count

SELECTED SAFETY INFORMATION Before you take NIVESTYMTM, tell your healthcare provider about all of your medical conditions, including if you: SELECTED SAFETY INFORMATION • have a sickle cell disorder How will I receive NIVESTYMTM? • have kidney problems • NIVESTYM TM injections can be given by a healthcare • are receiving radiation therapy provider by intravenous (IV) infusion or under your skin • are pregnant or plan to become pregnant. It is not known if (subcutaneous injection). Your healthcare provider may NIVESTYMTM will harm your unborn baby decide that subcutaneous injections can be given at home by you or your caregiver. If NIVESTYMTM is given at home, • are breastfeeding or plan to breastfeed. It is not known if see the detailed “Instructions for Use” that comes with NIVESTYMTM passes into your breast milk your NIVESTYMTM prescription for information on how to TM Tell your healthcare provider about all the medicines prepare and inject a dose of NIVESTYM you take, including prescription and over-the-counter • Your healthcare provider should show you and your caregiver medicines, vitamins, and herbal supplements. how to prepare and inject NIVESTYMTM before you use it • You should not try to inject a dose of NIVESTYMTM less than 0.3 mL (180 mcg) from a NIVESTYMTM prefilled syringe. Please see Important Safety Information and Indications on pages 8-11 and accompanying full Prescribing Information, A dose less than 0.3 mL cannot be accurately measured TM 2 including Patient Information. using the NIVESTYM prefilled syringe 3 Why would I be prescribed NIVESTYM?

If you are at a significant risk of developing severe neutropenia, your healthcare provider may prescribe WHAT IS A a granulocyte colony-stimulating factor (G-CSF) like NIVESTYM to help reduce the risk of infection in patients BIOSIMILAR? receiving certain chemotherapy regimens.

Neutropenia, which may be caused by some chemotherapy regimens, refers to an abnormally low level of a common NIVESTYM is a biosimilar to Neupogen® (filgrastim). type of white blood cell called a neutrophil. Neutrophils are important because they help fight off infections in the Biosimilars are FDA-approved, highly similar versions of body, and people with neutropenia are prone to infection existing biologic products, also known as reference because they don’t have enough of them. products. Biosimilars undergo a rigorous evaluation to demonstrate that there are no clinically meaningful differences in structure, function, efficacy, and safety What is a granulocyte colony-stimulating factor from their reference products. (G-CSF)?

G-CSF is a natural substance made by the body that Do biosimilars have the same side-effect and stimulates the bone marrow to produce neutrophils and safety profile as the reference product? help fight infection. Biosimilars have no meaningful differences in terms of Drug therapies like NIVESTYM are man-made forms safety and effectiveness compared to the products from of G-CSF that can help the bone marrow make more which they are derived (their “reference” product). For white blood cells. They are used to treat neutropenia, biosimilar products, FDA only allows minor differences including severe chronic neutropenia, help prevent in clinically inactive components. infection in patients with certain types of cancer, and prepare the blood for the collection of certain types of blood cells. How long have biosimilars been prescribed? SELECTED SAFETY INFORMATION How will I receive NIVESTYMTM? (cont’d) Biosimilars have been available outside the United States since first being introduced in Europe in 2007. The first biosimilar • Your healthcare provider will tell you how much was approved in the United States in 2015, and, as of 2018, TM NIVESTYM to inject and when to inject it. there are 10 available by prescription with at least 60 TM Do not change your dose or stop NIVESTYM in development. unless your healthcare provider tells you • If you are receiving NIVESTYMTM because you are also receiving chemotherapy, your dose of NIVESTYMTM should be injected at least 24 hours before or 24 hours after your dose of chemotherapy

Please see Important Safety Information and Indications on pages 8-11 and accompanying full Prescribing Information, 4 including Patient Information. 5 How will I receive NIVESTYM? How do I self-administer NIVESTYM?

NIVESTYM injections can be given by a healthcare Your healthcare provider should show you and your caregiver provider by intravenous (IV) infusion or under your how to prepare and inject NIVESTYM before you use it. skin (subcutaneous injection). Your healthcare See the detailed “Instructions for Use” that comes with provider may decide subcutaneous injections can your NIVESTYM prescription for information on how to be given at home by you or your caregiver. prepare and inject a dose of NIVESTYM. If NIVESTYM is given at home, see the detailed “Instructions for Use” that comes with your NIVESTYM prescription for information on how to prepare and inject a dose of NIVESTYM. Will my coverage allow me to receive NIVESTYM?

You should not inject a dose of NIVESTYM less NIVESTYM may be covered by your health insurance. than 0.3 mL (180 mcg) from a NIVESTYM TM prefilled syringe. A dose less than 0.3 mL cannot Pfizer Oncology Together can help you understand be accurately measured using the NIVESTYM your insurance and identify what financial support may prefilled syringe. be available for your prescribed NIVESTYM. See pages 12–14 of this brochure for more information Your healthcare provider will tell you how much about Pfizer Oncology Together. NIVESTYM to inject and when to inject it. Do not change your dose or stop NIVESTYM unless instructed by your healthcare provider.

If you are receiving NIVESTYM because you are also receiving chemotherapy, your dose of NIVESTYM should be injected at least 24 hours before or 24 hours after your dose of chemotherapy.

If you miss a dose of NIVESTYM, talk to your healthcare provider as soon as possible about when you should get your next dose.

SELECTED SAFETY INFORMATION SELECTED SAFETY INFORMATION How will I receive NIVESTYMTM? (cont’d) What are the possible side effects of NIVESTYMTM? • If you miss a dose of NIVESTYMTM, talk to your healthcare NIVESTYMTM may cause serious side effects, including: provider about when you should have your next dose • Spleen rupture. Your spleen may become enlarged and can rupture. A ruptured spleen can cause death. Call your healthcare provider right away if you Please see Important Safety Information and Indications on have pain in the left upper stomach (abdomen) pages 8-11 and accompanying full Prescribing Information, area or your left shoulder 6 including Patient Information. 7 IMPORTANT SAFETY INFORMATION • If you are receiving NIVESTYMTM because you are also AND INDICATIONS receiving chemotherapy, your dose of NIVESTYMTM should Do not take NIVESTYMTM if you have had a serious allergic be injected at least 24 hours before or 24 hours after your reaction to human granulocyte colony-stimulating factors dose of chemotherapy (G-CSFs) such as filgrastim products or pegfilgrastim products. • If you miss a dose of NIVESTYMTM, talk to your healthcare provider about when you should have your next dose Before you take NIVESTYMTM, tell your healthcare provider about all of your medical conditions, including if you: What are the possible side effects of NIVESTYMTM? • have a sickle cell disorder NIVESTYMTM may cause serious side effects, including: • have kidney problems • Spleen rupture. Your spleen may become enlarged and • are receiving radiation therapy can rupture. A ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left • are pregnant or plan to become pregnant. It is not known upper stomach (abdomen) area or your left shoulder if NIVESTYMTM will harm your unborn baby • A serious lung problem called acute respiratory distress • are breastfeeding or plan to breastfeed. It is not known if syndrome (ARDS). Call your healthcare provider or get TM NIVESTYM passes into your breast milk emergency medical help right away if you have shortness Tell your healthcare provider about all the medicines of breath with or without a fever, trouble breathing, or a you take, including prescription and over-the-counter fast rate of breathing medicines, vitamins, and herbal supplements. • Serious allergic reactions. NIVESTYMTM can cause serious allergic reactions. These reactions can cause a rash over How will I receive NIVESTYMTM? your whole body, shortness of breath, wheezing, dizziness, • NIVESTYM TM injections can be given by a healthcare swelling around your mouth or eyes, fast heart rate, and provider by intravenous (IV) infusion or under your sweating. If you have any of these symptoms, stop using skin (subcutaneous injection). Your healthcare provider NIVESTYMTM and call your healthcare provider or get may decide that subcutaneous injections can be given emergency medical help right away at home by you or your caregiver. If NIVESTYMTM is • Sickle cell crises. You may have a serious sickle cell crisis given at home, see the detailed “Instructions for Use” if you have a sickle cell disorder and receive NIVESTYMTM. that comes with your NIVESTYMTM prescription for Serious sickle cell crises have happened in people with information on how to prepare and inject a dose of sickle cell disorders receiving filgrastim that have NIVESTYMTM sometimes led to death. Call your healthcare provider • Your healthcare provider should show you and your caregiver right away if you have symptoms of sickle cell crisis such how to prepare and inject NIVESTYMTM before you use it as pain or difficulty breathing • You should not try to inject a dose of NIVESTYMTM less • Kidney injury (glomerulonephritis). NIVESTYMTM can than 0.3 mL (180 mcg) from a NIVESTYMTM prefilled cause kidney injury. Call your healthcare provider right syringe. A dose less than 0.3 mL cannot be accurately away if you develop any of the following symptoms: measured using the NIVESTYMTM prefilled syringe º swelling of your face or ankles TM • Your healthcare provider will tell you how much NIVESTYM º blood in your urine or dark-colored urine to inject and when to inject it. Do not change your dose or º you urinate less than usual stop NIVESTYMTM unless your healthcare provider tells you

Please see Important Safety Information here and continues on pages 10-11 and accompanying full Prescribing Information, 8 including Patient Information. 9 IMPORTANT SAFETY INFORMATION (CONT’D) You are encouraged to report adverse events related to Pfizer • Capillary leak syndrome. NIVESTYMTM can cause fluid products by calling 1-800-438-1985 (U.S. only). If you prefer, to leak from blood vessels into your body’s tissues. you may contact the U.S. Food and Drug Administration This condition is called “Capillary Leak Syndrome” (CLS). (FDA) directly. Visit http://www.fda.gov/MedWatch or call CLS can quickly cause you to have symptoms that may 1-800-FDA-1088. become life threatening. Get emergency medical help right away if you develop any of the following symptoms: INDICATIONS º swelling or puffiness and are urinating less than usual Patients with Cancer Receiving Myelosuppressive Chemotherapy º trouble breathing TM º swelling of your stomach area (abdomen) and feeling • NIVESTYM is indicated to decrease the incidence of of fullness infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive º dizziness or feeling faint a general feeling of tiredness anti-cancer drugs associated with a significant incidence of º severe neutropenia with fever • Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during Patients with Acute Myeloid Leukemia Receiving treatment with NIVESTYMTM. Tell your healthcare provider Induction or Consolidation Chemotherapy if you have unusual bleeding or bruising during treatment • NIVESTYM TM is indicated for reducing the time to neutrophil with NIVESTYMTM. This could be a sign of decreased recovery and the duration of fever, following induction or platelet counts, which may reduce the ability of your consolidation chemotherapy treatment of patients with acute blood to clot myeloid leukemia (AML) • Increased white blood cell count (leukocytosis). Patients with Cancer Undergoing Bone Marrow Your healthcare provider will check your blood during Transplantation TM treatment with NIVESTYM • NIVESTYM TM is indicated to reduce the duration of • Inflammation of your blood vessels (cutaneous vasculitis). neutropenia and neutropenia-related clinical sequelae‚ Tell your healthcare provider if you develop purple spots or eg, febrile neutropenia, in patients with nonmyeloid redness of your skin malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation • Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports Patients Undergoing Autologous Peripheral Blood blood from the heart to the body) may be caused by Progenitor Cell Collection and Therapy TM NIVESTYM . Symptoms may include fever, abdominal • NIVESTYM TM is indicated for the mobilization of autologous pain, feeling tired, and back pain. Call your healthcare hematopoietic progenitor cells into the peripheral blood for provider if you experience these symptoms collection by leukapheresis The most common side effects of NIVESTYMTM include Patients with Severe Chronic Neutropenia aching in the bones and muscles. These are not all the • NIVESTYM TM is indicated for chronic administration TM possible side effect of NIVESTYM . Call your healthcare to reduce the incidence and duration of sequelae of provider for medical advice about side effects. neutropenia (eg‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia

Please see Important Safety Information and Indications on pages 8-11 and accompanying full Prescribing Information, 10 including Patient Information. 11 If you are covered by Medicare or another government-funded program: Help identifying resources for eligible patients with Medicare, Medicaid, and other government insurance plans: • Assistance with searching for support from independent Making your support charitable foundations: These foundations exist independently needs a priority. of Pfizer and have their own eligibility criteria and application Together. processes. Availability of support from the foundations is determined solely by the foundations • Free medicine*

*If support from independent charitable foundations is not available, Pfizer Oncology Together will provide At Pfizer Oncology Together, we treat your individual needs eligible patients with medication for free through the as a priority. For eligible patients, we will help you find Pfizer Patient Assistance Program. The Pfizer Patient Assistance Program is a joint program of Pfizer Inc. and financial assistance options. We’ll also connect you with a the Pfizer Patient Assistance Foundation™. The Pfizer dedicated Care Champion who has social work experience Patient Assistance Foundation is a separate legal entity and can provide resources that may help with some of from Pfizer Inc. with distinct legal restrictions. your day-to-day challenges. If you are uninsured: Help identifying resources for eligible patients without any Learning about financial support. form of healthcare coverage: Together. • Help finding coverage • Free medicine through the Pfizer Patient Assistance Program Pfizer Oncology Together can help you understand your insurance and identify what financial support may be available for your prescribed NIVESTYM. Finding resources for your day-to-day. Together. If you are commercially insured: At Pfizer Oncology Together, our Care Champions, who have Resources for eligible commercial, private, employer, and state social work experience, can offer you resources that may help health insurance marketplace patients: with some of your day-to-day challenges†: • Connections to emotional support resources • The Pfizer Oncology Together Co-Pay Savings Program for Injectables provides eligible, commercially insured patients • Connections to an independent organization that helps prescribed NIVESTYM with assistance for their out-of-pocket eligible patients find rides and lodging for treatment-related appointments drug costs, including co-pays and coinsurance. Limits, terms, and conditions apply. See page 14. • Educational information on topics such as nutrition • Information to help you prepare for leaving or returning You may pay as little as $0 for each NIVESTYM treatment to work

The program covers up to $10,000 per calendar year †Some services are provided through third-party organizations that operate independently and are not controlled by Pfizer. Availability of services and eligibility There are no income requirements for patients to qualify requirements are determined solely by these organizations.

FOR LIVE, PERSONALIZED SUPPORT Please see Important Safety Information and Indications on Call 1-877-744-5675 (Monday–Friday 8 AM–8 PM ET) pages 8-11 and accompanying full Prescribing Information, LEARN MORE: Visit PfizerOncologyTogether.com 12 including Patient Information. 13 Pfizer Oncology Together Co-Pay Savings Program Terms and Conditions By using this program, you acknowledge that you currently meet the eligibility criteria and will comply with the terms and conditions below: • The Pfizer Oncology Together Co-Pay Savings Program for Injectables for NIVESTYM is not valid for patients that are enrolled in a state or federally funded insurance program, including but not limited to Medicare, Medicaid, TRICARE, Veterans Affairs health care, a state prescription drug assistance program, or the Government Health Insurance Plan available in Puerto Rico (formerly known as “La Reforma de Salud”). • Program offer is not valid for cash-paying patients. • With this program, eligible patients may pay as little as $0 co-pay per NIVESTYM treatment, subject to a maximum benefit of $10,000 per calendar year for out-of-pocket expenses for NIVESTYM including co-pays or coinsurances. • The amount of any benefit is the difference between your co-pay and $0. • After the maximum of $10,000 you will be responsible for the remaining monthly out-of-pocket costs. • Patient must have private insurance with coverage of NIVESTYM. • This offer is not valid when the entire cost of your prescription drug is eligible to be reimbursed by your private insurance plans or other private health or pharmacy benefit programs. • You must deduct the value of this assistance from any reimbursement request submitted to your private insurance plan, either directly by you or on your behalf. • You are responsible for reporting use of the program to any private insurer, health plan, or other third party who pays for or reimburses any part of the prescription filled using the program, as may be required. • You should not use the program if your insurer or health plan prohibits use of manufacturer co-pay assistance programs. • This program is not valid where prohibited by law. • This program cannot be combined with any other savings, free trial or similar offer for the specified prescription. • This program is not health insurance. • This program is good only in the U.S. and Puerto Rico. • This program is limited to 1 per person during this offering period and is not transferable. • No other purchase is necessary. • Data related to your redemption of the program assistance may be collected, analyzed, and shared with Pfizer, for market research and other purposes related to assessing Pfizer’s programs. Data shared with Pfizer will be aggregated and de-identified; it will be combined with data related to other assistance redemptions and will not identify you. • Pfizer reserves the right to rescind, revoke, or amend this program without notice. • This program may not be available to patients in all states. • For more information about Pfizer, visit www.pfizer.com. • For more information about the Pfizer Oncology Together Co-Pay Savings Program for Injectables, call 1-877-744-5675, or write to: Pfizer Oncology Together Co-Pay Savings Program for Injectables P.O. Box 220366, Charlotte, NC 28222 • Program terms will expire at the end of each calendar year. Before the calendar year ends, you will receive information and eligibility requirements for continued participation. Please see Important Safety Information and Indications on pages 8-11 and accompanying full Prescribing Information, including Patient Information.

NIVESTYM is a registered trademark of Pfizer Inc. Neupogen® is a registered trademark of Amgen, Inc.

PP-NIV-USA-0131-01 © 2019 Pfizer Inc. All rights reserved. November 2019 14 NIVESTYM- filgrastim-aafi injection, solution Pfizer Laboratories Div Pfizer Inc ------

Injection: 480 mcg/1.6 mL in a single-dose vial (3) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Prefilled Syringe NIVESTYM safely and effectively. See full prescribing Injection: 300 mcg/0.5 mL in a single-dose prefilled syringe (3) information for NIVESTYM. Injection: 480 mcg/0.8 mL in a single-dose prefilled syringe (3) NIVESTYM™ (filgrastim-aafi) injection, for subcutaneous or CONTRAINDICATIONS intravenous use Patients with a history of serious allergic reactions to human Initial U.S. Approval: 2018 granulocyte colony-stimulating factors such as filgrastim products or NIVESTYM (filgrastim-aafi) is biosimilar* to NEUPOGEN pegfilgrastim products. (4) (filgrastim). WARNINGS AND PRECAUTIONS INDICATIONS AND USAGE Fatal splenic rupture: Evaluate patients who report left upper NIVESTYM is a leukocyte growth factor indicated to abdominal or shoulder pain for an enlarged spleen or splenic Decrease the incidence of infection‚ as manifested by febrile rupture. (5.1) neutropenia‚ in patients with nonmyeloid malignancies receiving Acute respiratory distress syndrome (ARDS): Evaluate patients myelosuppressive anti-cancer drugs associated with a significant who develop fever and lung infiltrates or respiratory distress for incidence of severe neutropenia with fever. (1.1) ARDS. Reduce the time to neutrophil recovery and the duration of fever, Discontinue NIVESTYM in patients with ARDS. (5.2) following induction or consolidation chemotherapy treatment of Serious allergic reactions, including anaphylaxis: Permanently patients with acute myeloid leukemia (AML). (1.2) discontinue NIVESTYM in patients with serious allergic Reduce the duration of neutropenia and neutropenia-related reactions. (5.3) clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with Fatal sickle cell crises: Have occurred. (5.4) nonmyeloid malignancies undergoing myeloablative Glomerulonephritis: Evaluate and consider dose-reduction or chemotherapy followed by bone marrow transplantation (BMT). interruption of NIVESTYM if causality is likely. (5.5) (1.3) Mobilize autologous hematopoietic progenitor cells into the ADVERSE REACTIONS peripheral blood for collection by leukapheresis. (1.4) Most common adverse reactions in patients: Reduce the incidence and duration of sequelae of severe With nonmyeloid malignancies receiving myelosuppressive anti- neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in cancer drugs (≥ 5% difference in incidence compared to placebo) symptomatic patients with congenital neutropenia‚ cyclic are pyrexia, pain, rash, cough, and dyspnea. (6.1) neutropenia‚ or idiopathic neutropenia. (1.5) With AML (≥ 2% difference in incidence) are pain, epistaxis and rash. (6.1) DOSAGE AND ADMINISTRATION With nonmyeloid malignancies undergoing myeloablative Patients with cancer receiving myelosuppressive chemotherapy or chemotherapy followed by BMT (≥ 5% difference in incidence) is induction and/or consolidation chemotherapy for AML. rash. (6.1) Recommended starting dose is 5 mcg/kg/day subcutaneous Undergoing peripheral blood progenitor cell mobilization and injection, short intravenous infusion (15 to 30 minutes), or collection (≥ 5% incidence) are bone pain, pyrexia and headache. continuous intravenous infusion. See Full Prescribing (6.1) Information for recommended dosage adjustments and timing With severe chronic neutropenia (SCN) (≥ 5% difference in of administration. (2.1) incidence) are pain, anemia, epistaxis, diarrhea, hypoesthesia and Patients with cancer undergoing bone marrow transplantation. alopecia. (6.1) 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. See Full Prescribing Information for recommended dosage adjustments and timing of administration. (2.2) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or Patients undergoing autologous peripheral blood progenitor cell www.fda.gov/medwatch. collection and therapy. See 17 for PATIENT COUNSELING INFORMATION and FDA- 10 mcg/kg/day subcutaneous injection. (2.3) approved patient labeling. Administer for at least 4 days before first leukapheresis procedure and continue until last leukapheresis. (2.3) * Biosimilar means that the biological product is approved based on data Patients with congenital neutropenia. demonstrating that it is highly similar to an FDA-approved biological Recommended starting dose is 6 mcg/kg subcutaneous product, known as a reference product, and that there are no clinically injection twice daily. (2.4) meaningful differences between the biosimilar product and the reference Patients with cyclic or idiopathic neutropenia. product. Recommended starting dose is 5 mcg/kg subcutaneous Biosimilarity of NIVESTYM has been demonstrated for the condition(s)

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] injection daily. (2.4) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), Direct administration of less than 0.3 mL (180 mcg) using and route(s) of administration described in its Full Prescribing NIVESTYM prefilled syringe is not recommended due to potential Information. for dosing errors. (2.5) Revised: 7/2018

DOSAGE FORMS AND STRENGTHS Vial Injection: 300 mcg/mL in a single-dose vial (3)

FULL PRESCRIBING INFORMATION: 5.14 Nuclear Imaging CONTENTS* 5.15 Aortitis 1 INDICATIONS AND USAGE 6 ADVERSE REACTIONS 1.1 Patients with Cancer Receiving Myelosuppressive 6.1 Clinical Trials Experience Chemotherapy 6.2 Immunogenicity 1.2 Patients with Acute Myeloid Leukemia Receiving 6.3 Postmarketing Experience Induction or Consolidation Chemotherapy 8 USE IN SPECIFIC POPULATIONS 1.3 Patients with Cancer Undergoing Bone Marrow 8.1 Pregnancy Transplantation 8.2 Lactation 1.4 Patients Undergoing Autologous Peripheral Blood 8.4 Pediatric Use Progenitor Cell Collection and Therapy 8.5 Geriatric Use 1.5 Patients with Severe Chronic Neutropenia 10 OVERDOSAGE 2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION 2.1 Dosage in Patients with Cancer Receiving 12 CLINICAL PHARMACOLOGY Myelosuppressive Chemotherapy or Induction and/or 12.1 Mechanism of Action Consolidation Chemotherapy for AML 12.2 Pharmacodynamics 2.2 Dosage in Patients with Cancer Undergoing Bone 12.3 Pharmacokinetics Marrow Transplantation 13 NONCLINICAL TOXICOLOGY 2.3 Dosage in Patients Undergoing Autologous 13.1 Carcinogenesis, Mutagenesis, Impairment of Peripheral Blood Progenitor Cell Collection and Fertility Therapy 13.2 Animal Toxicology and Pharmacology 2.4 Dosage in Patients with Severe Chronic 14 CLINICAL STUDIES Neutropenia 14.1 Patients with Cancer Receiving 2.5 Important Administration Instructions Myelosuppressive Chemotherapy 3 DOSAGE FORMS AND STRENGTHS 14.2 Patients with Acute Myeloid Leukemia 4 CONTRAINDICATIONS Receiving Induction or Consolidation Chemotherapy 5 WARNINGS AND PRECAUTIONS 14.3 Patients with Cancer Undergoing Bone Marrow 5.1 Splenic Rupture Transplantation 5.2 Acute Respiratory Distress Syndrome 14.4 Patients Undergoing Autologous Peripheral 5.3 Serious Allergic Reactions Blood Progenitor Cell Collection and Therapy 5.4 Sickle Cell Disorders 14.5 Patients with Severe Chronic Neutropenia 5.5 Glomerulonephritis 16 HOW SUPPLIED/STORAGE AND HANDLING 5.6 Alveolar Hemorrhage and Hemoptysis 17 PATIENT COUNSELING INFORMATION 5.7 Capillary Leak Syndrome * Sections or subsections omitted from the full prescribing 5.8 Patients with Severe Chronic Neutropenia information are not listed. 5.9 Thrombocytopenia 5.10 Leukocytosis 5.11 Cutaneous Vasculitis 5.12 Potential Effect on Malignant Cells 5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy NIVESTYM is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever [see Clinical Studies (14.1)].

1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy NIVESTYM is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) [see Clinical Studies (14.2)].

1.3 Patients with Cancer Undergoing Bone Marrow Transplantation NIVESTYM is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies (14.3)].

1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy NIVESTYM is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4)].

1.5 Patients with Severe Chronic Neutropenia NIVESTYM is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia [see Clinical Studies (14.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of NIVESTYM is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection‚ by short intravenous infusion (15 to 30 minutes)‚ or by continuous intravenous infusion. Obtain a complete blood count (CBC) and platelet count before instituting NIVESTYM therapy and monitor twice weekly during therapy. Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the absolute neutrophil count (ANC) nadir. Recommend stopping NIVESTYM if the ANC increases beyond 10‚000/mm3 [see Warnings and Precautions (5.10)].

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Administer NIVESTYM at least 24 hours after cytotoxic chemotherapy. Do not administer NIVESTYM within the 24-hour period prior to chemotherapy [see Warnings and Precautions (5.13)]. A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of NIVESTYM therapy. Therefore, to ensure a sustained therapeutic response‚ administer NIVESTYM daily for up to 2 weeks or until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of NIVESTYM therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.

2.2 Dosage in Patients with Cancer Undergoing Bone Marrow Transplantation The recommended dosage of NIVESTYM following bone marrow transplantation (BMT) is 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. Administer the first dose of NIVESTYM at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Monitor CBCs and platelet counts frequently following marrow transplantation. During the period of neutrophil recovery‚ titrate the daily dosage of NIVESTYM against the neutrophil response (see Table 1).

Table 1. Recommended Dosage Adjustments During Neutrophil Recovery in Patients with Cancer Following BMT Absolute Neutrophil Count NIVESTYM Dosage Adjustment When ANC greater than 1000/mm3 Reduce to 5 mcg/kg/day* for 3 consecutive days Then, if ANC remains greater than 1000/mm3 for 3 more consecutive Discontinue NIVESTYM days Then, if ANC decreases to less than Resume at 5 mcg/kg/day 1000/mm3 * If ANC decreases to less than 1000/mm3 at any time during the 5 mcg/kg/day administration‚ increase NIVESTYM to 10 mcg/kg/day‚ and then follow the above steps.

2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy The recommended dosage of NIVESTYM for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer NIVESTYM for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of NIVESTYM administration and leukapheresis schedule have not been established‚ administration of filgrastim for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective [see Clinical Studies (14.4)]. Monitor neutrophil counts after 4 days of NIVESTYM‚ and discontinue NIVESTYM if the white blood cell (WBC) count rises to greater than 100‚000/mm3 .

2.4 Dosage in Patients with Severe Chronic Neutropenia Prior to starting NIVESTYM in patients with suspected chronic neutropenia, confirm the diagnosis of severe chronic neutropenia (SCN) by evaluating serial CBCs with differential and platelet counts‚ and evaluating bone marrow morphology and karyotype. The use of NIVESTYM prior to confirmation of a correct diagnosis of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition‚ other than SCN‚ causing the neutropenia.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] The recommended starting dosage in patients with Congenital Neutropenia is 6 mcg/kg as a twice daily subcutaneous injection and the recommended starting dosage in patients with Idiopathic or Cyclic Neutropenia is 5 mcg/kg as a single daily subcutaneous injection.

Dosage Adjustments in Patients with Severe Chronic Neutropenia Chronic daily administration is required to maintain clinical benefit. Individualize the dosage based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of filgrastim were: 6 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of filgrastim greater than or equal to 100 mcg/kg/day.

Monitor CBCs for Dosage Adjustments During the initial 4 weeks of NIVESTYM therapy and during the 2 weeks following any dosage adjustment‚ monitor CBCs with differential and platelet counts. Once a patient is clinically stable‚ monitor CBCs with differential and platelet counts monthly during the first year of treatment. Thereafter, if the patient is clinically stable, less frequent routine monitoring is recommended.

2.5 Important Administration Instructions Patient self-administration and administration by a caregiver may benefit from training by a healthcare professional. Training should aim to demonstrate to those patients and caregivers how to measure the dose using the prefilled syringe, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use of NIVESTYM prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NIVESTYM [see Instructions for Use]. NIVESTYM prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard is not designed to allow for direct administration of doses of less than 0.3 mL (180 mcg). The spring-mechanism of the needle guard apparatus affixed to the prefilled syringe interferes with the visibility of the graduation markings on the syringe barrel corresponding to 0.1 mL and 0.2 mL. The visibility of these markings is necessary to accurately measure doses of NIVESTYM less than 0.3 mL (180 mcg) for direct administration. Thus, the direct administration to patients requiring doses of less than 0.3 mL (180 mcg) is not recommended due to the potential for dosing errors. For direct administration of doses less than 0.3 mL (180 mcg) use NIVESTYM single-dose vial. NIVESTYM is supplied in single-dose vials (for subcutaneous use or intravenous infusion) and single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths (3)]. Prior to use‚ remove the vial or prefilled syringe from the refrigerator and allow NIVESTYM to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours. Discard any vial or prefilled syringe left at room temperature for greater than 24 hours. Visually inspect NIVESTYM for particulate matter and discoloration prior to administration (the solution is clear and colorless). Do not administer NIVESTYM if particulates or discoloration are observed. Discard unused portion of NIVESTYM in vials or prefilled syringes; do not re-enter the vial. Do not save unused drug for later administration.

Subcutaneous Injection Inject NIVESTYM subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer NIVESTYM, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the vial or prefilled syringe [see Patient Counseling Information (17)]. Training by the healthcare provider should aim to demonstrate to those patients and caregivers how to measure the dose of NIVESTYM, and the focus should be on ensuring that a patient or caregiver can successfully perform all of

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] the steps in the Instructions for Use for the vial or prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NIVESTYM or whether the patient would benefit from a different NIVESTYM presentation. If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the NIVESTYM prefilled syringe, use of the NIVESTYM vial may be considered. If the patient or caregiver misses a dose of NIVESTYM, instruct them to contact their healthcare provider.

Administration Instructions for the Prefilled Syringe The NIVESTYM syringe plunger stopper and needle cover are not made with natural rubber latex.

Administration Instructions for Dilution (Vial Only) If required for intravenous administration‚ NIVESTYM (vial only) may be diluted in 5% Dextrose Injection, USP from a concentration of 300 mcg/mL to 5 mcg/mL (do not dilute to a final concentration less than 5 mcg/mL). NIVESTYM diluted to concentrations from 5 mcg/mL to 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% Dextrose Injection, USP or 5% Dextrose plus Albumin (Human)‚ NIVESTYM is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes. Do not dilute with saline at any time because the product may precipitate. Diluted NIVESTYM solution can be stored at room temperature for up to 24 hours. This 24 hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

3 DOSAGE FORMS AND STRENGTHS

Vial: Injection: 300 mcg/mL of a clear, colorless solution in a single-dose vial Injection: 480 mcg/1.6 mL of a clear, colorless solution in a single-dose vial

Prefilled Syringe: Injection: 300 mcg/0.5 mL of a clear, colorless solution in a single-dose prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard Injection: 480 mcg/0.8 mL of a clear, colorless solution in a single-dose prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard

4 CONTRAINDICATIONS NIVESTYM is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony- stimulating factors such as filgrastim products or pegfilgrastim products [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NIVESTYM in patients with ARDS.

5.3 Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NIVESTYM in patients with serious allergic reactions. NIVESTYM is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim.

5.4 Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NIVESTYM if sickle cell crisis occurs.

5.5 Glomerulonephritis Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of NIVESTYM.

5.6 Alveolar Hemorrhage and Hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products for peripheral blood progenitor cell (PBPC) \ mobilization. Hemoptysis resolved with discontinuation of filgrastim products. The use of NIVESTYM for PBPC mobilization in healthy donors is not an approved indication.

5.7 Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.8 Patients with Severe Chronic Neutropenia Confirm the diagnosis of SCN before initiating NIVESTYM therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim products administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing NIVESTYM should be carefully considered.

5.9 Thrombocytopenia Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

5.10 Leukocytosis

Patients with Cancer Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving NIVESTYM as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that NIVESTYM therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of NIVESTYM that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of filgrastim therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.

Peripheral Blood Progenitor Cell Collection and Therapy During the period of administration of NIVESTYM for PBPC mobilization in patients with cancer, discontinue NIVESTYM if the leukocyte count rises to > 100,000/mm3 .

5.11 Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold NIVESTYM therapy in patients with cutaneous vasculitis. NIVESTYM may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

5.12 Potential Effect on Malignant Cells NIVESTYM is a growth factor that primarily stimulates neutrophils. The granulocyte-colony-stimulating factor (G- CSF) receptor through which NIVESTYM acts has also been found on tumor cell lines. The possibility that NIVESTYM acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When NIVESTYM is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of NIVESTYM given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use NIVESTYM in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration (2.2)].

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] The safety and efficacy of NIVESTYM have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NIVESTYM with chemotherapy and radiation therapy.

5.14 Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. This should be considered when interpreting bone-imaging results.

5.15 Aortitis Aortitis has been reported in patients receiving filgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue NIVESTYM if aortitis is suspected.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Splenic Rupture [see Warnings and Precautions (5.1)] Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] Serious Allergic Reactions [see Warnings and Precautions (5.3)] Sickle Cell Disorders [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6)] Capillary Leak Syndrome [see Warnings and Precautions (5.7)] Thrombocytopenia [see Warnings and Precautions (5.9)] Leukocytosis [see Warnings and Precautions (5.10)] Cutaneous Vasculitis [see Warnings and Precautions (5.11)] Aortitis [see Warnings and Precautions (5.15)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with: small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1) small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3).

A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m2 (Study 1), 240 mcg/m2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1%

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Asian.

Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo) System Organ Class Filgrastim Placebo Preferred Term (N = 294) (N = 157) Blood and lymphatic system disorders Thrombocytopenia 38% 29% Gastrointestinal disorders Nausea 43% 32% General disorders and administration site conditions Pyrexia 48% 29% Chest pain 13% 6% Pain 12% 6% Fatigue 20% 10% Musculoskeletal and connective tissue disorders Back pain 15% 8% Arthralgia 9% 2% Bone pain 11% 6% Pain in extremity* 7% 3% Nervous system disorders Dizziness 14% 3% Respiratory, thoracic and mediastinal disorders Cough 14% 8% Dyspnea 13% 8% Skin and subcutaneous tissue disorders Rash 14% 5% Investigations Blood lactate dehydrogenase increased 6% 1% Blood alkaline phosphatase increased 6% 1% * Percent difference (Filgrastim – Placebo) was 4%.

Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male. Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular. http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4 hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24 hour infusion (Study 6) filgrastim (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male. Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity. Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

Table 3. Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients) System Organ Class Mobilization Phase Preferred Term (N = 166) Musculoskeletal and connective tissue disorders Bone pain 30% General disorders and administration site conditions Pyrexia 16% Investigations Blood alkaline phosphatase increased 11% Nervous system disorders Headache 10%

Adverse Reactions in Patients with Severe Chronic Neutropenia The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4 month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of filgrastim was determined by the category of neutropenia. Initial

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] dosage of filgrastim: Idiopathic neutropenia: 3.6 mcg/kg/day Cyclic neutropenia: 6 mcg/kg/day Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to filgrastim in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The incidence of antibody development in patients receiving filgrastim products has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim products, the nature and specificity of these antibodies has not been adequately studied. In clinical studies using filgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of filgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)] acute respiratory distress syndrome [see Warnings and Precautions (5.2)] anaphylaxis [see Warnings and Precautions (5.3)] sickle cell disorders [see Warnings and Precautions (5.4)] glomerulonephritis [see Warnings and Precautions (5.5)] alveolar hemorrhage and hemoptysis [see Warnings and Precautions (5.6)] capillary leak syndrome [see Warnings and Precautions (5.7)] leukocytosis [see Warnings and Precautions (5.10)] cutaneous vasculitis [see Warnings and Precautions (5.11)] Sweet's syndrome (acute febrile neutrophilic dermatosis) decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with filgrastim products.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Risk Summary There are no adequate and well-controlled clinical studies in pregnant women, therefore the potential risk to the fetus with the use of filgrastim products is unknown. Reports in the scientific literature have described transplacental passage of filgrastim in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). In animal reproduction studies, effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. No maternal or fetal effects were observed in pregnant rats at doses up to 58 times the human doses. Filgrastim been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Human data Several observational studies based on the Severe Chronic Neutropenia International Registry (SCNIR) described pregnancy outcomes in women with severe chronic neutropenia (SCN) who were exposed to filgrastim products during pregnancy and women with SCN who were unexposed. No major differences were seen between treated and untreated women with respect to pregnancy outcome (including miscarriage and preterm labor), newborn complications (including birth weight) and infections. Methodological limitations of these studies, include small sample size, and lack of generalizability due to the underlying maternal condition.

Animal data Effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day, which is approximately 58 times higher than the human dose of 10 mcg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day).

8.2 Lactation

Risk Summary There is published literature documenting transfer of filgrastim products into human milk. There are a few case reports describing the use of filgrastim products in breastfeeding mothers with no adverse effects noted in the infants. There are no data on the effects of filgrastim products on milk production. Other recombinant filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NIVESTYM and any potential adverse effects on the breastfed child from NIVESTYM or from the underlying maternal condition.

8.4 Pediatric Use NIVESTYM prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard may not accurately measure volumes less than 0.3 mL due to the needle spring mechanism design. Therefore, the direct administration of a volume less http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] than 0.3 mL using NIVESTYM prefilled syringe is not recommended due to the potential for dosing errors. For direct administration of doses less than 0.3 mL (180 mcg) use NIVESTYM single-dose vial. In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 to 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous filgrastim at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8). The pharmacokinetics of filgrastim in pediatric patients after chemotherapy were similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim. In this population‚ filgrastim was well-tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with filgrastim therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population. The safety and effectiveness of filgrastim have been established in pediatric patients with SCN [see Clinical Studies (14.5)]. In a phase 3 study (Study 7) to assess the safety and efficacy of filgrastim in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow- up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage (1.5), Dosage and Administration (2.5), and Clinical Studies (14.5)]. Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of filgrastim treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function. Pediatric patients with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic filgrastim treatment. The relationship of these events to filgrastim administration is unknown [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

8.5 Geriatric Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of filgrastim-treated patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Clinical studies of filgrastim in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

10 OVERDOSAGE The maximum tolerated dose of filgrastim products has not been determined. In filgrastim clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects. Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day.

11 DESCRIPTION Filgrastim-aafi is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] NIVESTYM is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. NIVESTYM has a molecular weight of 18‚799 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli. Because NIVESTYM is produced in E coli‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell. NIVESTYM is a sterile‚ clear‚ colorless‚ preservative-free liquid containing filgrastim-aafi injection for subcutaneous or intravenous use. The product is available in single-dose vials and prefilled syringes. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim-aafi. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-aafi. See Table 4 below for product composition of each single-dose vial or prefilled syringe.

Table 4. Product Composition 300mcg/mL 480 mcg/1.6 mL 300 mcg/0.5 mL 480 mcg/0.8 mL Vial Vial Syringe Syringe Filgrastim-aafi 300 mcg 480 mcg 300 mcg 480 mcg Acetate 0.59 mg 0.94 mg 0.295 mg 0.472 mg Polysorbate 80 0.04 mg 0.064 mg 0.02 mg 0.032 mg Sodium 0.035 mg 0.056 mg 0.0175 mg 0.028 mg Sorbitol 50 mg 80 mg 25 mg 40 mg Water for Injection USP 1 mL 1.6 mL 0.5 mL 0.8 mL q.s. ad* * quantity sufficient to make

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation. Endogenous G-CSF is a lineage-specific colony-stimulating factor that is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody-dependent killing, and the increased expression of some cell surface antigens). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage.

12.2 Pharmacodynamics In phase 1 studies involving 96 patients with various non-myeloid malignancies‚ filgrastim administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. This increase in neutrophil counts was observed whether filgrastim was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/kg/day). With discontinuation of filgrastim therapy‚ neutrophil counts returned to baseline in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin)

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] activity in vitro. The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving filgrastim; however‚ the percentage of monocytes in the differential count remained within the normal range. Absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of filgrastim. Increases in lymphocyte counts following filgrastim administration have been reported in some normal subjects and patients with cancer. White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection.

12.3 Pharmacokinetics Filgrastim products exhibit nonlinear pharmacokinetics. Clearance is dependent on filgrastim product concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of filgrastim products and is diminished by neutropenia. In addition, filgrastim products are cleared by the kidney. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and cancer subjects. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following filgrastim dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 to 20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated. The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.

Specific Populations

Pediatric Patients The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim [see Use in Specific Populations (8.4)].

Renal Impairment In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (n = 4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, NIVESTYM dose adjustment for in patients with hepatic impairment is not necessary.

13 NONCLINICAL TOXICOLOGY

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of filgrastim products has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats at doses up to 500 mcg/kg.

13.2 Animal Toxicology and Pharmacology Filgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a nonclinical toxicology program, which included studies up to 1 year duration. In the repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of filgrastim (i.e.‚ dose-dependent increases in white blood cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bone marrow). Histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis, and dose-related increases in spleen weight were seen in all species. These changes all reversed after discontinuation of treatment.

14 CLINICAL STUDIES

14.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The safety and efficacy of filgrastim to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs were established in a randomized‚ double-blind‚ placebo-controlled trial conducted in patients with small cell lung cancer (Study 1). In Study 1, patients received up to 6 cycles of intravenous chemotherapy including intravenous cyclophosphamide and doxorubicin on day 1; and etoposide on days 1, 2, and 3 of 21 day cycles. Patients were randomized to receive filgrastim (n = 99) at a dose of 230 mcg/m2 (4 to 8 mcg/kg/day) or placebo (n = 111). Study drug was administered subcutaneously daily beginning on day 4, for a maximum of 14 days. A total of 210 patients were evaluable for efficacy and 207 were evaluable for safety. The demographic and disease characteristics were balanced between arms with a median age of 62 (range 31 to 80) years; 64% males; 89% Caucasian; 72% extensive disease and 28% limited disease. The main efficacy endpoint was the incidence of febrile neutropenia. Febrile neutropenia was defined as an ANC < 1000/mm3 and temperature > 38.2°C. Treatment with filgrastim resulted in a clinically and statistically significant reduction in the incidence of infection‚ as manifested by febrile neutropenia, 40% for filgrastim -treated patients and 76% for placebo-treated patients (p < 0.001). There were also statistically significant reductions in the incidence and overall duration of infection manifested by febrile neutropenia; the incidence, severity and duration of severe neutropenia (ANC < 500/mm3 ); the incidence and overall duration of hospital admissions; and the number of reported days of antibiotic use.

14.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy The safety and efficacy of filgrastim to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, double-blind‚ placebo-controlled‚ multi-center trial in patients with newly diagnosed, de novo AML (Study 4). In Study 4 the initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous filgrastim (n = 259) at a dose of 5 mcg/kg/day or placebo (n = 262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC ≥ 1000/mm3 for 3 consecutive days or ≥ 10,000/mm3 for 1 day) or for a maximum of 35 days. The demographic and disease characteristics were balanced between arms with a median age of 54 (range 16 to 89) years; 54% males; initial white blood cell count (65% < 25,000/mm3 and 27% > 100,000/mm3 ); 29% unfavorable

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] cytogenetics. The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm3 . Treatment with filgrastim resulted in a clinically and statistically significant reduction in median number of days of severe neutropenia, filgrastim -treated patients 14 days, placebo-treated patients 19 days (p = 0.0001: difference of 5 days (95% CI: -6.0, -4.0)). There was a reduction in the median duration of intravenous antibiotic use, filgrastim -treated patients: 15 days versus placebo-treated patients: 18.5 days; a reduction in the median duration of hospitalization, filgrastim-treated patients: 20 days versus placebo-treated patients: 25 days. There were no statistically significant differences between the filgrastim and the placebo groups in complete remission rate (69% - filgrastim, 68% - placebo), median time to progression of all randomized patients (165 days - filgrastim, 186 days - placebo), or median overall survival (380 days - filgrastim, 425 days - placebo).

14.3 Patients with Cancer Undergoing Bone Marrow Transplantation The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of patients with lymphoma (Study 6 and Study 9). The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo controlled trial (Study 10). In Study 6 patients with Hodgkin's disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU ("CVP"), and patients with non-Hodgkin's lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan ("BEAM"). There were 54 patients randomized 1:1:1 to control, filgrastim 10 mcg/kg/day, and filgrastim 30 mcg/kg/day as a 24 hour continuous infusion starting 24 hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin's disease and 31% non-Hodgkin's lymphoma. The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm3 . A statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3 ) occurred in the filgrastim -treated groups versus the control group (23 days in the control group‚ 11 days in the 10 mcg/kg/day group, and 14 days in the 30 mcg/kg/day group [11 days in the combined treatment groups‚ p = 0.004]). In Study 9, patients with Hodgkin's disease and non-Hodgkin's lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU ("CVP"). There were 43 evaluable patients randomized to continuous subcutaneous infusion filgrastim 10 mcg/kg/day (n = 19), filgrastim 30 mcg/kg/day (n = 10) and no treatment (n = 14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin's disease and 72% non-Hodgkin's lymphoma. The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3 ) in the filgrastim-treated groups versus the control group (21.5 days in the control group versus 10 days in the filgrastim -treated groups, p < 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group versus 5 days in the filgrastim--treated groups‚ p < 0.0001). In Study 10, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive filgrastim 300 mcg/m2 /day (n = 33) or placebo (n = 37) days 5 through 28 after marrow infusion. The median age was 18 (range 1 to 45) years, 56% males. The underlying disease was: 67% hematologic malignancy, 24% aplastic anemia, 9% other. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group‚ p < 0.001) and time to recovery of ANC to ≥ 500/mm3 (21 days in the control group and 16 days in the treatment group‚ p < 0.001).

14.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] The safety and efficacy of filgrastim to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using filgrastim mobilized autologous peripheral blood progenitor cells to autologous bone marrow (Study 11). Patients in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 7 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dose of filgrastim ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion. Engraftment was evaluated in 64 patients who underwent transplantation using filgrastim mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count ≥ 20‚000/mm3 by day 28. In clinical trials of filgrastim for the mobilization of hematopoietic progenitor cells‚ filgrastim was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (≥ 500/mm3 ) was reached. The rate of engraftment of these cells in the absence of filgrastim post transplantation has not been studied. Study 11 was a randomized, unblinded study of patients with Hodgkin's disease or non-Hodgkin's lymphoma undergoing myeloablative chemotherapy‚ 27 patients received filgrastim-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. The preparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan ("BEAM"). Patients received daily filgrastim 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin's disease and 43% non-Hodgkin's lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to filgrastim-mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs 10 days).

14.5 Patients with Severe Chronic Neutropenia The safety and efficacy of filgrastim to reduce the incidence and duration of sequelae of neutropenia (that is fever‚ infections, oropharyngeal ulcers) in symptomatic adult and pediatric patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia was established in a randomized controlled trial conducted in patients with severe neutropenia (Study 7). Patients eligible for Study 7 had a history of severe chronic neutropenia documented with an ANC < 500/mm3 on three occasions during a 6 month period, or in patients with cyclic neutropenia 5 consecutive days of ANC < 500/mm3 per cycle. In addition, patients must have experienced a clinically significant infection during the previous 12 months. Patients were randomized to a 4 month observation period followed by filgrastim treatment or immediate filgrastim treatment. The median age was 12 years (range 7 months to 76 years); 46% males; 34% idiopathic, 17% cyclic and 49% congenital neutropenia. Filgrastim was administered subcutaneously. The dose of filgrastim was determined by the category of neutropenia. Initial dose of filgrastim: Idiopathic neutropenia: 3.6 mcg/kg/day Cyclic neutropenia: 6 mcg/kg/day Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dose was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. The main efficacy endpoint was response to filgrastim treatment. ANC response from baseline (< 500/mm3 ) was defined as follows: Complete response: median ANC > 1500/mm3 Partial response: median ANC ≥ 500/mm3 and ≤ 1500/mm3 with a minimum increase of 100% No response: median ANC < 500/mm3

There were 112 of 123 patients who demonstrated a complete or partial response to filgrastim treatment. Additional efficacy endpoints included a comparison between patients randomized to 4 months of observation and patients receiving filgrastim of the following parameters:

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] incidence of infection incidence of fever duration of fever incidence, duration, and severity of oropharyngeal ulcers number of days of antibiotic use

The incidence for each of these 5 clinical parameters was lower in the filgrastim arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. An analysis of variance showed no significant interaction between treatment and diagnosis‚ suggesting that efficacy did not differ substantially in the different diseases. Although filgrastim substantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚ cycling persisted but the period of neutropenia was shortened to 1 day.

16 HOW SUPPLIED/STORAGE AND HANDLING

Vials Injection: Single-dose vials containing 300 mcg/mL of a sterile, clear, colorless, preservative-free filgrastim-aafi solution. Dispensing packs of 10 vials (NDC 0069-0293-10). Injection: Single-dose vials containing 480 mcg/1.6 mL (300 mcg/mL) of a sterile, clear, colorless, preservative-free filgrastim-aafi solution. Dispensing packs of 10 vials (NDC 0069-0294-10).

Prefilled Syringes Injection: Single-dose prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard, containing 300 mcg/0.5 mL of a sterile, clear, colorless, preservative-free filgrastim-aafi solution. Pack of 1 prefilled syringe (NDC 0069-0291-01). Pack of 10 prefilled syringes (NDC 0069-0291-10).

Injection: Single-dose, prefilled syringe with BD UltraSafe Plus™ Passive Needle Guard, containing 480 mcg/0.8 mL of a sterile, clear, colorless, preservative-free filgrastim-aafi solution. Pack of 1 prefilled syringe (NDC 0069-0292-01). Pack of 10 prefilled syringes (NDC 0069-0292-10).

The NIVESTYM syringe plunger stopper and needle cover are not made with natural rubber latex [see Dosage and Administration (2.5)].

Storage Store NIVESTYM in the refrigerator at 2° to 8°C (36° to 46°F) in the original carton to protect from light. Do not leave NIVESTYM in direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard NIVESTYM if frozen more than once. Avoid shaking. Transport via a pneumatic tube has not been studied.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of NIVESTYM vial and prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NIVESTYM or whether the patient would benefit from a http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] different NIVESTYM presentation. Advise patients of the following risks and potential risks with NIVESTYM: Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their physician immediately [see Warnings and Precautions (5.1)]. Dyspnea, with or without fever, progressing to Acute Respiratory Distress Syndrome, may occur. Advise patients to report dyspnea to their physician immediately [see Warnings and Precautions (5.2)]. Serious allergic reactions may occur, which may be signaled by rash‚ facial edema‚ wheezing‚ dyspnea‚ hypotension‚ or tachycardia. Advise patients to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions (5.3)]. In patients with sickle cell disease, sickle cell crisis and death have occurred. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of human granulocyte colony-stimulating factors [see Warnings and Precautions (5.4)]. Glomerulonephritis may occur. Symptoms include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their physician immediately [see Warnings and Precautions (5.5)]. Cutaneous vasculitis may occur, which may be signaled by purpura or erythema. Advise patients to report signs or symptoms of vasculitis to their physician immediately [see Warnings and Precautions (5.11)]. Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increase inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately [see Warnings and Precautions (5.15)].

Instruct patients who self-administer NIVESTYM using the prefilled syringe or single-dose vial of the: Importance of following the applicable Instructions for Use. Dangers of reusing needles, syringes, or unused portions of single-dose vials. Importance of following local requirements for proper disposal of used syringes, needles, and unused vials. Importance of informing the healthcare provider if difficulty occurs when measuring or administering partial contents of the NIVESTYM prefilled syringe. If difficulty occurs, use of the NIVESTYM vial may be considered. Difference in product concentration of the NIVESTYM prefilled syringe in comparison to the NIVESTYM vial. When switching patients from the NIVESTYM prefilled syringe to the NIVESTYM vial, or vice versa, ensure that patients understand the correct volume to be administered since the concentration of NIVESTYM differs between the prefilled syringe and the vial.

This product's label may have been updated. For full prescribing information, please visit www.pfizer.com.

Manufactured by: Hospira, Inc., a Pfizer Company Lake Forest, IL 60045 USA US License No. 1974 LAB-0933-1.0

Patient Information NIVESTYM (Neye-ves-tim) (filgrastim-aafi) http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] injection What is NIVESTYM? NIVESTYM is a man-made form of granulocyte colony-stimulating factor (G-CSF). G-CSF is a substance produced by the body. It stimulates the growth of neutrophils, a type of white blood cell important in the body's fight against infection. Do not take NIVESTYM if you have had a serious allergic reaction to human G-CSFs such as filgrastim products or pegfilgrastim products. Before you take NIVESTYM, tell your healthcare provider about all of your medical conditions, including if you: have a sickle cell disorder. have kidney problems. are receiving radiation therapy. are pregnant or plan to become pregnant. It is not known if NIVESTYM will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if NIVESTYM passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive NIVESTYM? NIVESTYM injections can be given by a healthcare provider by intravenous (IV) infusion or under your skin (subcutaneous injection). Your healthcare provider may decide subcutaneous injections can be given at home by you or your caregiver. If NIVESTYM is given at home, see the detailed "Instructions for Use" that comes with your NIVESTYM for information on how to prepare and inject a dose of NIVESTYM. You and your caregiver should be shown how to prepare and inject NIVESTYM before you use it, by your healthcare provider. You should not try to inject a dose of NIVESTYM less than 0.3 mL (180 mcg) from a NIVESTYM prefilled syringe. A dose less than 0.3 mL cannot be accurately measured using the NIVESTYM prefilled syringe. Your healthcare provider will tell you how much NIVESTYM to inject and when to inject it. Do not change your dose or stop NIVESTYM unless your healthcare provider tells you to. If you are receiving NIVESTYM because you are also receiving chemotherapy, your dose of NIVESTYM should be injected at least 24 hours before or 24 hours after your dose of chemotherapy. If you miss a dose of NIVESTYM, talk to your healthcare provider about when you should give your next dose.

What are the possible side effects of NIVESTYM? NIVESTYM may cause serious side effects, including: Spleen rupture. Your spleen may become enlarged and can rupture. A ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach (abdomen) area or your left shoulder. A serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider or get emergency medical help right away if you have shortness of breath with or without a fever, trouble breathing, or a fast rate of breathing. Serious allergic reactions. NIVESTYM can cause serious allergic reactions. These reactions can cause a rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using NIVESTYM and call your healthcare provider or get emergency medical help right away. Sickle cell crises. You may have a serious sickle cell crisis if you have a sickle cell disorder and receive NIVESTYM. Serious sickle cell crises have happened in people with sickle cell disorders receiving filgrastim that has sometimes led to death. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing. Kidney injury (glomerulonephritis). NIVESTYM can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms: swelling of your face or ankles blood in your urine or dark colored urine

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] you urinate less than usual Capillary leak syndrome. NIVESTYM can cause fluid to leak from blood vessels into your body's tissues. This condition is called "Capillary Leak Syndrome" (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms: swelling or puffiness and are urinating less than usual trouble breathing swelling of your stomach-area (abdomen) and feeling of fullness dizziness or feeling faint a general feeling of tiredness Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with NIVESTYM. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with NIVESTYM. This could be a sign of decreased platelet counts, which may reduce the ability of your blood to clot. Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with NIVESTYM. Inflammation of your blood vessels (cutaneous vasculitis). Tell your healthcare provider if you develop purple spots or redness of your skin. Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) may be caused by NIVESTYM. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.

The most common side effects of NIVESTYM include aching in the bones and muscles. These are not all the possible side effects of NIVESTYM. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NIVESTYM? Store NIVESTYM in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze. Keep NIVESTYM in the original carton to protect from light or physical damage. Do not shake NIVESTYM. Take NIVESTYM out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. Throw away (dispose of) any NIVESTYM that has been left at room temperature for longer than 24 hours. After you inject your dose, throw away (dispose of) any unused NIVESTYM left in the vials or prefilled syringes. Do not save unused NIVESTYM in the vials or prefilled syringes for later use.

Keep NIVESTYM out of the reach of children. General information about the safe and effective use of NIVESTYM. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NIVESTYM for a condition for which it was not prescribed. Do not give NIVESTYM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NIVESTYM that is written for healthcare professionals. What are the ingredients in NIVESTYM? Active ingredient: (filgrastim-aafi) Inactive ingredients: acetate, polysorbate 80, sodium, sorbitol, and water for Injection Manufactured by Hospira, Inc., a Pfizer Company, Lake Forest, IL 60045 USA US License No. 1974 LAB-0935-1.0 For more information go to www.pfizer.com or call 1-800-438- 1985. This Patient Information has been approved by the U.S. Food and Revised: July 2018 Drug Administration http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Instructions for Use NIVESTYM (Neye-ves-tim) (filgrastim-aafi) injection Single-Dose Prefilled Syringe Important Read the Patient Information for important information you need to know about NIVESTYM before using this Instructions for Use. Before you use a NIVESTYM prefilled syringe, read this important information.

Storing your prefilled syringe

Store the NIVESTYM prefilled syringe in the refrigerator between 36˚F to 46˚F (2˚C to 8˚C). Do not freeze. Keep the NIVESTYM prefilled syringe in the original carton to protect from light or physical damage. Take the prefilled syringe out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. The NIVESTYM prefilled syringe may be allowed to reach room temperature for up to 24 hours. Throw away (dispose of) any NIVESTYM prefilled syringe that has been left at room temperature for longer than 24 hours. After you inject your dose, throw away (dispose of) any unused NIVESTYM left in the prefilled syringe. Do not save unused NIVESTYM in the prefilled syringe for later use. Keep NIVESTYM and all medicines out of the reach of children.

Using your prefilled syringe

It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider. You should not inject a dose of NIVESTYM less than 0.3 mL (180 mcg) from a NIVESTYM prefilled syringe. A dose less than 0.3 mL cannot be accurately measured using the NIVESTYM prefilled syringe. Make sure the name NIVESTYM appears on the carton and prefilled syringe label. Do not use a NIVESTYM prefilled syringe after the expiration date on the label. Do not shake the NIVESTYM prefilled syringe. The prefilled syringe has a needle guard that needs to be activated to cover the needle after the injection is given. The needle guard will help prevent needle stick injuries to anyone who handles the prefilled syringe. Do not remove the needle cover from the prefilled syringe until you are ready to inject. Do not use the NIVESTYM prefilled syringe if the needle cover is missing. Do not use the prefilled syringe if the carton is open or damaged. Do not use a prefilled syringe if it has been dropped on a hard surface. The prefilled syringe may be broken even if you cannot see the break. Use a new prefilled syringe.

Call your healthcare provider if you have any questions.

About the NIVESTYM prefilled syringe

NIVESTYM prefilled syringes come in two strengths. Depending on your prescription, you will receive NIVESTYM prefilled syringes that contain 300 mcg/0.5mL or 480 mcg/0.8mL of medicine. Your healthcare http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] provider will determine the dose in milliliters (mL) that you will need to give based on your body weight. When you receive your NIVESTYM prefilled syringes, always check to see that the: name NIVESTYM appears on the carton and prefilled syringe label. expiration date on the prefilled syringe label has not passed. You should not use a prefilled syringe after the date on the label. strength of NIVESTYM (number of micrograms on the carton containing the prefilled syringe) is the same as what your healthcare provider prescribed.

NIVESTYM prefilled syringe parts (see Figure A). NIVESTYM 300 mcg/0.5mL prefilled syringe is shown as an example.

Figure A

What you need for your injection

Included in the carton: 1 new NIVESTYM prefilled syringe

Not included in the carton (see Figure B) 1 adhesive bandage 1 alcohol wipe 1 cotton ball or gauze sharps disposal container

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Figure B

Figure C shows a needle guard that has not yet been activated. The prefilled syringe is ready for use. This is what the prefilled syringe looks like before use.

Figure C

Figure D shows a needle guard that has been activated. This is what the prefilled syringe looks like after use.

Figure D

Preparing the NIVESTYM prefilled syringe

Step 1: Find a clean, well-lit flat work surface. Take the carton containing the NIVESTYM prefilled syringe out of the refrigerator and leave it unopened on your work surface for at least 30 minutes so that it reaches room temperature. Put the original carton with any unused prefilled syringes back in the refrigerator. Step 2: Do not shake the prefilled syringe. Do not leave the prefilled syringe in direct sunlight.

Step 3: Wash your hands with soap and water. Remove the prefilled syringe from the carton. Check to make sure that the needle guard is covering the barrel of the prefilled syringe. Do not push the needle guard over the needle cover before the injection. This may activate or lock the needle guard. See Figure C above that shows how the prefilled syringe looks before Step 4: use. If the needle guard is covering the needle that means it has been activated. See Figure D above that shows how the prefilled syringe looks after use. Do not use the NIVESTYM prefilled syringe. Get another prefilled syringe that has not been activated and is ready to use. Check the expiration date on the NIVESTYM prefilled syringe. Do not use the NIVESTYM prefilled Step 5: syringe if the expiration date has passed. Inspect the medicine and prefilled syringe. Turn the prefilled syringe so you can see the medicine and markings in the window. Look through the window on the NIVESTYM prefilled syringe. Make sure the

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] medicine in the prefilled syringe is clear and colorless. Do not use the NIVESTYM prefilled syringe if: The medicine is cloudy or discolored or contains flakes or particles. Step 6: Any part of the prefilled syringe appears cracked or broken. The prefilled syringe has been dropped. The needle cover is missing or not securely attached. The expiration date printed on the label has passed. In all cases, use a new prefilled syringe and call your healthcare provider.

Choose the injection site When giving your injections, follow your healthcare provider's instructions about changing the site for each injection. Areas of your body that you may use as injection sites include (See Figure E): front of your thigh stomach area (abdomen), except for a 2-inch area around your navel (belly button) outer upper outer arms, only if a caregiver is giving you the injection upper outer area of your buttocks, only if a caregiver is giving you the injection

Step 7:

Figure E

Choose a different site for each injection of NIVESTYM. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.

Clean your injection site with an alcohol wipe. See Figure F. Let your skin dry. Do not touch this area again before injecting.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Step 8:

Figure F

Hold the prefilled syringe by the needle guard with the needle cover pointing up. Carefully pull the needle Step 9: cover straight off and away from your body. Throw away the needle cover. Do not recap the needle. See Figure G.

Figure G

Your healthcare provider has prescribed either a "full" syringe dose or a "partial" syringe dose.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] If you are prescribed a partial dose of NIVESTYM, follow Steps 10 through 18. If you are prescribed a full dose, you will inject all of the medicine from your prefilled syringe. For a full dose, skip Steps 10 and 11, and follow Steps 12 through 18.

Partial dosing

Step Point the needle up and tap gently until the air rises to the top. See Figure H. 10:

Figure H

Holding the prefilled syringe as shown, slowly push up on the plunger rod to push out the extra air and medicine until the end of the conical base (edge) of the plunger stopper lines up with the syringe marking for your prescribed dose. See Figure I for an example of a dose of 0.3 mL. Your dose may be different than the Step example shown. 11: Be careful not to activate the needle guard before use. Do not use a NIVESTYM prefilled syringe that has been activated. Check again to make sure the correct dose of NIVESTYM is in the prefilled syringe.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Figure I

Administering the NIVESTYM prefilled syringe

Step With one hand, gently pinch a fold of skin at the injection site. Hold the pinch. See Figure J. 12:

Figure J

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] With your other hand, hold the prefilled syringe like you would hold a pencil. Use a quick "dart-like" Step 13: motion to insert the needle at a 45 to 90 degree angle into the skin as shown. See Figure K.

Figure K

Using slow and constant pressure, press down on the plunger rod as far as it will go. Keep the plunger rod Step 14: fully pressed down while you hold the prefilled syringe in place for 5 seconds. See Figure L.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Figure L

Step Keep the plunger rod fully pressed down while you carefully pull the needle straight out from the injection 15: site. See Figure M.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Figure M

As you let go of the plunger rod, the needle guard will automatically slide over the needle until the needle is Step 16: completely covered and the needle guard locks into place. Do not recap the needle. See Figure N.

Figure N

There may be a small amount of blood at the injection site. You can press a cotton ball or gauze over the Step injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a 17: small adhesive bandage, if needed. See Figure O.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Figure O

Throw away (dispose of) the syringe as instructed by your healthcare provider or by following the Step 18: instructions below. See Figure P.

Figure P

Disposing of (throw away) used NIVESTYM prefilled syringes

Put the used prefilled syringe in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) prefilled syringes in your household trash.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Hospira, Inc., a Pfizer Company Lake Forest, IL 60045 USA US License No. 1974

LAB-0938-1.0 For more information go to www.pfizer.com or call 1-800-438-1985. Issued: July 2018

Instructions for Use NIVESTYM (Neye-ves-tim) (filgrastim-aafi) injection Single-Dose Vial Important Read the Patient Information for important information you need to know about NIVESTYM before using these Instructions for Use. Before you use a NIVESTYM vial, read this important information: Storing your NIVESTYM vial Store the vial in the refrigerator between 36˚F to 46˚F (2˚C to 8˚C). Do not freeze. Keep the vial in the original carton to protect from light or physical damage. Take the vial out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. Throw away (dispose of) any vial that has been left at room temperature for longer than 24 hours. After you inject your dose, throw away (dispose of) any unused NIVESTYM left in the vial. Do not save unused NIVESTYM in the vial for later use.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Keep NIVESTYM and all medicines out of the reach of children. Using your vial It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider. Make sure the name NIVESTYM appears on the carton and vial label. Only use the vial 1 time. Discard (throw away) the vial with any remaining NIVESTYM liquid. Do not use a vial after the expiration date on the label. Do not shake the vial. Do not use the vial if the medicine is cloudy or discolored or contains flakes or particles.

Call your healthcare provider if you have any questions. Step 1: Prepare

A Remove the vial from the refrigerator. Find a clean, well-lit, flat work surface. Place the vial on your clean work surface for 30 minutes and allow it to reach room temperature before you give an injection. Do not try to warm the vial by using a heat source such as hot water or microwave. Do not leave the vial in direct sunlight. Do not shake the vial. Use the vial only 1 time.

B Inspect the vial. Make sure the medicine in the vial is clear and colorless. Do not use the vial if: The medicine is cloudy or discolored or contains flakes or particles. The expiration date printed on the label has passed. In all cases, use a new vial and call your healthcare provider.

C Gather all materials needed for your injection. Wash your hands thoroughly with soap and water. On your clean, well-lit, flat work surface, place: 1 Vial 1 Disposable syringe and needle 2 Alcohol wipes 1 Cotton ball or gauze pad 1 Adhesive bandage Sharps disposal container

Only use the disposable syringes and needles that your healthcare provider prescribes. Only use the syringes and needles 1 time. Throw away (dispose of) any used syringes and needles. See Step 5 Finish, for instructions about how to properly dispose of used syringes and needles.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] You should only use a syringe that is marked in tenths of milliliters (mL). Your healthcare provider will show you how to measure the correct dose of NIVESTYM. This dose will be measured in milliliters (mL).

Step 2: Get Ready

D Take the cap off the vial. Clean the rubber stopper with 1 alcohol wipe.

E Check the carton containing the needle and syringe. If the carton has been opened or damaged, do not use that needle and syringe. Dispose of (throw away) that needle and syringe in the sharps disposal container. F Hold the syringe by the barrel with the needle cap pointing up. Carefully pull the needle cap straight off and away from your body.

Pull back on the plunger and draw air into the syringe that is the same amount (mL) as the dose of NIVESTYM that your healthcare provider prescribed.

Important: Throw away the needle cap into the sharps disposal container. Do not recap the needle.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] G Keep the vial on the flat work surface and insert the needle straight down through the rubber stopper. Do not insert the needle through the rubber stopper more than 1 time. H Push the plunger down and inject all the air from the syringe into the vial of NIVESTYM.

I Keep the needle in the vial and turn the vial upside down. Make sure that the NIVESTYM liquid is covering the tip of the needle.

J Keep the vial upside down and slowly pull back on the plunger to fill the syringe barrel with NIVESTYM to the

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] correct marking amount (mL) of medicine that matches the dose your healthcare provider prescribed. K Keep the needle in the vial and check for air bubbles in the syringe. If there are air bubbles, gently tap the syringe barrel with your finger until the air bubbles rise to the top. Slowly push the plunger up to push the air bubbles out of the syringe.

L Keep the tip of the needle in the liquid and again pull the plunger back to the number on the syringe barrel that matches your dose. Check again for air bubbles. The air in the syringe will not hurt you, but too large an air bubble can reduce your dose of NIVESTYM. If there are still air bubbles, repeat the steps above to remove them. M Check again to make sure that you have the correct dose in the syringe. It is important that you use the exact dose prescribed by your healthcare provider. Do not remove the needle from the vial. Lay the vial down on its side with the needle still in the vial.

Step 3: Select and Prepare the Injection Site

N Prepare and clean your injection site.

You can use: Thigh

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Stomach area (abdomen), except for a 2-inch area right around your navel (belly button) Upper outer area of your buttocks (only if someone else is giving you the injection) Outer area of upper arm (only if someone else is giving you the injection)

Clean your injection site with a clean alcohol wipe. Let your skin dry. Do not touch this area again before injecting. If you want to use the same injection site, make sure it is not the same spot on the injection site area you used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.

Step 4: Subcutaneous (under the skin) injection

O Remove the prepared syringe and needle from the vial. P Pinch your injection site to create a firm surface.

Important: Keep skin pinched while injecting.

Q Hold the pinch. Insert the needle into the skin at a 45 to 90 degree angle.

R Using slow and constant pressure, push the plunger until it reaches the bottom.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] When done gently pull the needle out of the injection site at the same 45 to 90 degree angle used to insert it.

Step 5: Finish

S Dispose of (throw away) the used needle and syringe.

http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles, and syringes in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

T Examine the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply an adhesive bandage if needed.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Hospira, Inc., a Pfizer Company Lake Forest, IL 60045 USA US License No. 1974

LAB-0937-1.0 For more information go to www.pfizer.com or call 1-800-438-1985. Issued: July 2018

Revised: 7/2018 Pfizer Laboratories Div Pfizer Inc http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM] http://labeling.pfizer.com/ShowLabeling.aspx?id=10899[8/20/2018 9:09:08 PM]